Mechanisms of dual modulatory effects of spermine on the mitochondrial calcium uniporter complex

The mitochondrial Ca²⁺ uniporter is the Ca²⁺ channel responsible for mitochondrial Ca²⁺ uptake. It plays crucial physiological roles in regulating oxidative phosphorylation, intracellular Ca²⁺ signaling, and cell death. The uniporter contains the pore-forming MCU subunit, the auxiliary EMRE protein, and the regulatory MICU1 subunit, which blocks the MCU pore under resting cellular Ca²⁺ concentrations. It has been known for decades that spermine, a biological polyamine ubiquitously present in animal cells, can enhance mitochondrial Ca²⁺ uptake, but the underlying mechanisms remain incompletely understood. In this study, we demonstrate that spermine exerts both potentiation and inhibitory effects on the uniporter. At physiological concentrations, spermine binds to membranes and disrupts MCU-MICU1 interactions, thereby opening the uniporter to import more Ca²⁺. However, at millimolar concentrations, spermine also inhibits the uniporter by targeting the pore-forming region in a MICU1-independent manner. These findings provide molecular insights into how cells can use spermine to control the critical processes of mitochondrial Ca²⁺ signaling and homeostasis.